The current research assessed the extent to which substance use behaviors (i.e., heavy episodic drinking, marijuana use, and use of illicit drugs other than marijuana) were associated with behaviors that confer risk for HIV infection (i.e., sex with multiple partners, inconsistent condom use, and injection drug use) in a nationally representative sample of young adults. Generalized estimating equations (GEEs) examined patterns in the data from U.S. young adults (N = 7,595), ages 21 to 30, who participated in the Monitoring the Future (MTF) panel study between 2004 and 2009. Fifty-two percent of the participants were female and 70% were White. Time-varying effects indicated that more frequent heavy episodic drinking, marijuana use, and other illicit drug use were associated with a greater number of sex partners. Frequency of marijuana and other illicit drug use was associated with less frequent condom use, and marijuana use was associated with use of injection drugs. Younger individuals (i.e., 21-24 years old versus 25-30 years old) had fewer sexual partners, more frequent condom use, and a stronger association between heavy episodic drinking and number of sexual partners than did older individuals. These effects did not vary across gender. Findings highlight the covariation of substance use with HIV-related risk factors among recent cohorts of young adults in the U. S. and the particularly strong link between heavy episodic drinking and number of sexual partners among individuals aged 21 to 24. Prevention programs should acknowledge the co-occurring risks of substance use and HIV risk behaviors, especially among young adults in their early twenties.